Anchoring Interferon Alpha to Apolipoprotein A-I Reduces Hematological Toxicity While Enhancing Immunostimulatory Properties

作者：Fioravanti Jessica; Gonzalez Iranzu; Medina Echeverz Jose; Larrea Esther; Ardaiz Nuria; Gonzalez Aseguinolaza Gloria; Prieto Jesus; Berraondo Pedro^*

来源：Hepatology, 2011, 53(6): 1864-1873.

DOI：10.1002/hep.24306

Interferon alpha (IFN alpha) is widely used for the treatment of viral hepatitis but substantial toxicity hampers its clinical use. In this work, we aimed at improving the efficacy of IFN alpha therapy by increasing the IFN alpha half-life and providing liver tropism. We selected apolipoprotein A-I (ApoA-I) as the stabilizing and targeting moiety. We generated plasmids encoding IFN alpha, albumin bound to IFN alpha (ALF), or IFN alpha linked to ApoA-I (IA) and mice were treated either by hydrodynamic administration of the plasmids or by injection of the corresponding recombinant proteins or high-density lipoproteins containing IA. The plasma half-life of IA was intermediate between IFN alpha and ALF. IA was targeted to the liver and induced higher hepatic expression of interferon-stimulated genes than IFN alpha or even ALF. IA exhibits stronger in vivo antiviral activity than IFN alpha and the hematologic cytopenic effects of IA are milder than those observed when using IFN alpha or ALF. In contrast to IFN alpha, IA does not cause activation-dependent cell death of lymphocytes in vitro. Accordingly, in vivo studies showed that IA boosts T-cell immune responses more efficiently than IFN alpha or ALF. The difference in immunostimulatory activity between IFN alpha and IA disappears in scavenger receptor class B type I (SR-BI) knockout mice, suggesting that crosstalk between SR-BI and IFN alpha receptor is essential for enhanced induction of cytotoxic T cells by IA. Conclusion: Anchoring IFN alpha to ApoA-I prolongs the half-life of IFN alpha and promotes targeting to the liver. Importantly, the fusion protein shows increased immunostimulatory properties and lower hematological toxicity. (HEPATOLOGY 2011;53:1864-1873)

• 出版日期2011-6